@article{c4ef1224571c4ad2bdc2ea271238d4d2,
title = "Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis",
abstract = "Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.",
keywords = "BMP-SMAD signaling, CP: Cancer, TP53, androgen receptor signaling, prostate cancer",
author = "Hyunho Han and Yan Wang and Josue Curto and Sreeharsha Gurrapu and Sara Laudato and Alekya Rumandla and Goutam Chakraborty and Xiaobo Wang and Hong Chen and Yan Jiang and Dhiraj Kumar and Caggiano, {Emily G.} and Monica Capogiri and Boyu Zhang and Yan Ji and Maity, {Sankar N.} and Min Hu and Shanshan Bai and Aparicio, {Ana M.} and Eleni Efstathiou and Logothetis, {Christopher J.} and Nicholas Navin and Navone, {Nora M.} and Yu Chen and Giancotti, {Filippo G.}",
note = "Funding Information: This work was supported by NIH grants R35 CA197566 (F.G.G.), U01 CA224044 (N.N. and Y.C.), U54CA224079 (Y.C.), P30 CA016672 (MDACC), and P30CA008748 (MSKCC); by CPRIT Recruitment of Established Investigators Award RR160031 (F.G.G.); by the generous philanthropic contributions to the UT MD Anderson Moon Shots Program (F.G.G. and C.J.L.); by the KHIDI grant for research under the Biomedical Global Talent Nurturing Program HI19C0723 (H.H.); and by DOD PCRP Early Investigator Research Award W81XWH-20-1-0217 (S.G.). We thank P. Shepherd for the propagation of PDX models, the CPRIT Single Cell Genomics Core (RP180684) for support with single-cell sequencing experiments, and members of the Giancotti laboratory for discussions. F.G.G. H.H. and Y.W. conceived the study, designed and analyzed experiments, and wrote the manuscript. H.H. and Y.W. performed most of the experiments. S.G. X.W. and E.G.C. helped with enzalutamide treatment experiments. S.G. A.R. and X.W. studied TP53- and BRCA1-silenced LNCaP cells. H.H. and S.B. performed scRNA-seq experiments and J.C. pharmacological inhibition experiments. G.C. and S.G. performed experiments on BMP signaling and A.R. S.L. and Y. Jiang in vitro functional assays. H.C. and M.H. helped with bioinformatics analyses and N.N. with scRNA-seq. D.K. B.Z. and S.G. characterized reprogramming of the PDX model. S.N.M. performed histological analysis of the PDXs. A.R. S.L. and S.G. characterized the Ptenpc−/− PC cells. X.W. helped with ChIP-seq; Y. Ji, A.R. and B.Z. generated reagents and animals; and N.M.N. S.N.M. and A.M.A. provided PDXs and transcriptome data. E.E. and C.J.L. provided access to the transcriptome data from the abi-enza neoadjuvant trial. Y.C. provided patient-derived organoids and critical insight. F.G.G. declares no competing interests. E.E. is a formal advisor to Janssen, Sanofi Merck, Novartis, Roche, Myovant, Pfizer, Astellas, AAA, and Astra Zeneca, and she has research fundings from Astellas, Janssen, and Pfizer. C.J.L. is an advisor with honoraria to Merck, Sharp & Dohme, Bayer, and Amgen, and he receives clinical grants from Janssen, ORIC Pharmaceuticals, Novartis, and Aragon Pharmaceuticals. Y.C. has stock ownership and received royalties from Oric Pharmaceuticals. Funding Information: This work was supported by NIH grants R35 CA197566 (F.G.G.), U01 CA224044 (N.N. and Y.C.), U54CA224079 (Y.C.), P30 CA016672 (MDACC), and P30CA008748 (MSKCC); by CPRIT Recruitment of Established Investigators Award RR160031 (F.G.G.); by the generous philanthropic contributions to the UT MD Anderson Moon Shots Program (F.G.G. and C.J.L.); by the KHIDI grant for research under the Biomedical Global Talent Nurturing Program HI19C0723 (H.H.); and by DOD PCRP Early Investigator Research Award W81XWH-20-1-0217 (S.G.). We thank P. Shepherd for the propagation of PDX models, the CPRIT Single Cell Genomics Core ( RP180684 ) for support with single-cell sequencing experiments, and members of the Giancotti laboratory for discussions. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
day = "5",
doi = "10.1016/j.celrep.2022.110595",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}